The overall goal of the program described in this competing submission proposal (CA47179-15) is to continue an integrated multidisciplinary approach to the investigation of the biology, pathogenesis, progression and natural history of soft tissue sarcoma and then use this knowledge to identify novel therapeutic targets that can be tested clinically in phase I and II clinical trials. The specific goals are to: 1) improve diagnosis and prognostication 2) identify new molecular and biochemical targets in sarcoma through gene discovery and pathway analysis 3) develop new targeted molecular therapeutics and 4) validate molecular and biochemical targets in clinical studies. To achieve these goals we have marshaled an integrated, multidisciplinary group of investigators all armed with a unique resource, a clinicopathological and outcomes database prospectively collected over a 23 year period containing over 6486 patients treated for soft tissue sarcoma at MSKCC. This database has been linked to an institutional tissue bank for the past 12 years and, for the past 3 years, to a comprehensive tissue procurement process for establishment of primary sarcoma cell lines and mouse xenograft models of human sarcoma. This renewal application contains substantial changes with the addition of two entirely new projects, which interact closely with the two continuing projects and the establishment of a new bioinformatics core. In Project 1, a new initiative in liposarcoma biology, we will use an integrated gene expression and NMR biochemical analysis to improve diagnosis and prognostication and to identify new therapeutic targets and cellular pathways critical to liposarcoma tumorigenesis. In Project 2, we will study how the PTEN/AKT signaling network regulates genes in the RB and p53 pathway to control cell cycle and apoptosis. Project 3, an entirely new project on development of targeted therapeutics, will identify new therapies that modulate the cell cycle and translate these preclinical discoveries into clinical cancer therapy for sarcoma patients. In Project 4, we will continue to define the molecular genetics of synovial sarcoma with a particular emphasis on identification of new molecular targets through mutational analysis of differentially expressed tyrosine kinase genes. These 4 projects are supported by 3 cores: Administrative, Pathology, and Bioinformatics. The highly integrated collaboration between all projects and cores will ensure maximum productivity and will enhance molecular and biochemical target identification through gene discovery and pathway analysis. This information will then be used to develop new targeted molecular therapeutics for soft tissue sarcoma.